Carotid Artery Stenting Versus Carotid Artery Endarterectomy in Asymptomatic Severe Carotid Stenosis: An Updated Meta-Analysis

Carotid artery stenting (CAS) and carotid artery endarterectomy (CEA) are revascularization options for the management of severe carotid disease in asymptomatic patients. We aimed to compare the peri-procedural outcomes of the two modalities. A systematic review of the databases PUBMED, EBSCO, and Cochrane Library was performed. All the studies that reported periprocedural outcomes (within 30 days) in asymptomatic carotid stenosis patients were included in the meta-analysis. Random effects models with inverse-variance weighting were used to estimate pooled risk ratios (RRs) to compare the outcomes. Fifteen studies (including seven randomized controlled trials) met the inclusion criteria. A total of 15251 patients were included, out of which 6419 (42%) underwent CAS and 8832 (57.9%) underwent CEA. There was no statistical difference in the primary composite outcome of death/stroke/myocardial infarction (MI) (RR 1.02, 95% CI [0.69-1.51], p 0.93). No difference was found in the secondary outcome of all-cause mortality. CAS was associated with a slightly lower risk of MI and cranial nerve palsy. CAS was associated with a slightly higher risk of stroke with no difference in the occurrence of disabling stroke or ipsilateral stroke. In general terms, the study confirms equipoise in the two treatment strategies with a higher risk of MI and cranial nerve palsy with CEA and a higher risk of non-disabling stroke with CAS.


Introduction And Background
Stroke is one of the leading causes of mortality and morbidity in the United States and is associated with high morbidity [1].About 15% of strokes are caused by atherosclerosis of the extracranial carotid artery [2].Asymptomatic carotid artery stenosis (ACAS) is defined as a ≥50% narrowing of the carotid artery in the absence of retinal or cerebral ischemia in the preceding six months.Based on age and gender, the prevalence of asymptomatic carotid stenosis ranges from 0.5% to 7% in the general population [3].A recent metaanalysis evaluating the risk of stroke in this population found the incidence of stroke to be as high as 4.3% in patients with high-risk plaque features [4].Revascularization with either carotid artery endarterectomy (CEA) or carotid artery stenting (CAS) plays an important role in stroke prevention.The most recent 2011 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on Management of Patients with Extracranial Carotid and Vertebral Artery Disease recommends CEA as first-line therapy, with CAS as a reasonable alternative in symptomatic patients [5].This consensus guideline also states that it is reasonable to perform revascularization in asymptomatic patients who have more than 70% stenosis of the internal carotid artery (ICA) if the risk of perioperative stroke, myocardial infarction (MI), and death is low.They recommend choosing CEA in older patients and CAS when CEA cannot be performed due to unfavorable anatomy [5].Similarly, the 2017 European Society of Cardiology guidelines recommend CEA to be performed in asymptomatic patients with an increased risk of stroke if the perioperative risk is <3% [6].Further, they recommend CAS in high-risk (Class IIa) and average-risk patients (Class IIb) when CEA cannot be performed [6].
In recent years, CAS has been proposed as a safer alternative due to the lower risk of cranial nerve palsy and cardiovascular complications.Nevertheless, there is a concern for an increased risk of perioperative stroke with CAS [7].However, with further advancements including the introduction of embolic protection devices, this risk appears to be significantly reduced.A study by Kastrup et al. showed that the use of an embolic protection device during CAS led to a statistically significant reduction in the occurrence of both major and minor strokes from 1.1% to 0.3% and from 3.7% to 0.5%, respectively [8].A recent meta-analysis comparing the two modalities showed a lower risk of MI but a non-significant trend toward an increased risk of periprocedural stroke with CAS [9].Since the publication of this meta-analysis, new data has emerged comparing the safety and efficacy of CAS with CEA.Due to conflicting literature and the emergence of new data in the field, we aimed to perform an updated systematic review and meta-analysis comparing the periprocedural outcomes of the two modalities for the management of asymptomatic severe carotid stenosis.
The preliminary results of our meta-analysis were presented at the 2022 Society for Cardiovascular Angiography & Interventions (SCAI) Annual Meeting on May 19, 2022.

Data Sources and Search Strategy
The recent Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed to design the study [10].Electronic databases including PubMed, EBSCO, and Cochrane Central Register of Controlled Trials (CENTRAL), were systematically searched using a combination of standardized medical subject headings (MeSH) and keywords including "carotid stenosis", "carotid endarterectomy", and "carotid stenting".The search items were combined using Boolean operators ("OR" or "AND").No filters including publication year, publication design, or language were applied.In addition, reference lists of all retrieved studies were searched manually for potentially relevant studies not found in the initial search.

Study Selection and Data Extraction
Two independent authors initially screened studies using the title and abstract followed by reading the full text of the selected articles for data extraction.Disagreements were resolved by consensus.We included fulllength articles published in the English language that compared outcomes of CAS and CEA in asymptomatic patients with severe carotid artery stenosis.All extracted data from the included studies were collected into a spreadsheet and verified by a third author.Data regarding baseline characteristics including mean age, gender, and presence of comorbidities outcomes were collected.The primary outcome of interest was a composite of periprocedural (within 30 days of index procedure) death/any stroke/MI.Secondary outcomes included all-cause mortality, any stroke, disabling stroke, ipsilateral stroke, MI, and cranial nerve palsy.Quality assessment was performed by two independent reviewers using the Cochrane Risk of Bias Tool and New Castle Ottawa (NOS) scale [11,12].

Statistical Analysis
The statistical analysis was performed using the Cochran-Mantel-Haenszel method under the randomeffects model to calculate the risk ratio using DerSimonian and Laird random effects model [13,14].The estimated effect size was reported as a point estimate and 95% confidence interval (CI).An alpha criterion of a p-value < 0.05 was considered statistically significant.Higgins's I-squared (I2) statistical model was used to evaluate variations in the outcomes of included studies [15].I2 values of 25%, 50%, and > 75% indicated low, moderate, and large amounts of heterogeneity, respectively.A sensitivity analysis was done using a fixed effect model.All statistical analysis was performed using the Cochrane Review Manager (RevMan v5.3,The Cochrane Collaboration, Oxford, UK) [16].

Results
A total of 3512 articles were identified after our initial search.After the removal of duplicates (n=580), the articles were screened using their titles and abstracts.Seventy-five articles were deemed relevant for fulltext review after the initial screening.Based on inclusion criteria, a total of 17 studies were found eligible.Out of these, one study was excluded as the full manuscript was not available in English, and one study was excluded due to a lack of reporting of any primary or secondary outcomes pertinent to the analysis in asymptomatic patients (Figure 1) [17,18].PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses Thus, a total of 15 studies comprising seven randomized controlled trials [19][20][21][22][23][24][25], five retrospective studies [26][27][28][29][30], one study with combined prospective and retrospective data [31], and two prospective nonrandomized studies [32,33] were included in the final analysis.Table 1 summarizes the characteristics of these studies.

Quality Assessment
Cochrane Collaboration's tool and NOS scale were used to assess the risk of bias and quality of randomized controlled trials (RCTs) and observational studies respectively.The overall risk of bias was found to be low.On visual assessment, there was no significant asymmetry noted on the funnel plot indicating a low risk of publication bias (Figure 2).A total of 15251 patients were included, out of which 6419 (42%) underwent CAS and 8832 (57.9%) underwent CEA.In the pooled analysis, the baseline characteristics of the two intervention groups were found to be similar (Table 2).The proportion of females was 29.2% (CAS) and 26.3% (CEA).The prevalence of comorbidities like diabetes (31.5% vs 31.1%),hypertension (65.3% vs 68.3%), dyslipidemia (54% vs 54.5%), and smoking (45.4% vs 37.2%) were similar in the CAS vs CEA groups.

Sensitivity Analysis
Sensitivity analysis performed using fixed effect models for both primary and secondary outcomes revealed similar results.

Discussion
A recent JAMA meta-analysis revealed that the overall incidence of ipsilateral stroke in patients with asymptomatic carotid stenosis (3.2%) is higher than the previously reported rate of 1% [4].The incidence is even higher (4.3%) in patients with features of high-risk plaques [4].Current guidelines recommend revascularization as a reasonable approach for stroke prevention in high-risk asymptomatic patients.The best choice of intervention however remains controversial with constant advancement in techniques and the emergence of new data, thus mandating the need to reevaluate revascularization strategies for carotid artery stenosis.We evaluated all the currently available data including the most recent and the largest study comparing the safety of these two interventions [19].
Our analysis revealed no significant statistical difference in the primary composite outcome of death/MI/any periprocedural stroke.CAS offers the benefit of lower risk of MI and cranial nerve palsy as has been demonstrated in other meta-analyses [9,34].We found a slightly higher albeit statistically significant risk of periprocedural stroke with CAS.In the pooled analysis, the increased risk of stroke was mainly driven by non-disabling stroke.The previous meta-analyses had revealed a non-significant increased risk of stroke with CAS [9,34].In our analysis, the statistical significance was mainly driven by ASCT 2 which had reported higher event rates in both groups as compared to the other major trials.However, there was no increased risk of ipsilateral stroke or disabling stroke.The ipsilateral strokes are thought to be associated with catheter manipulation and thus are affected by operator experience.This is also the explanation proposed by authors in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) trial for their overall low rates of stroke compared to other trials.Studies assessing operator experience have shown that the outcomes with carotid stenting including perioperative stroke and mortality are lower with experienced operators regardless of their specialty [35,36].The risk of stroke has also been shown to be associated with lesion characteristics.A study by Moore et al. found that the risk was higher in long lesions and/or sequential remote lesions [37].The authors concluded that the safety of CAS was comparable to CEA in the absence of these high-risk lesion characteristics.In addition, the long-term outcomes have been found to be similar in the two groups in a previous meta-analysis by Moresoli et al. [34].Jung et al. performed a pooled analysis to compare the long-term durability of the two procedures.They reported that despite the increased periprocedural risk of stroke, CAS is comparable to CEA in regard to long-term restenosis or occlusion rates [38].
The major strength of our study is that it is thus far the largest and most comprehensive meta-analysis including both real-world data and data from RCTs.Our findings confirmed the previously generally accepted clinical equipoise amongst the two modalities in terms of efficacy in the revascularization of asymptomatic severe carotid stenosis.The superiority of one modality over the other could not be established.Our study had some limitations as well.There was some heterogeneity in the definition of severe asymptomatic stenosis across different studies.Due to a lack of available data, we were unable to account for differences in other possible confounders including operator experience, types of stents used, medications used, and use of embolic protection devices.Long-term outcomes could not be pooled for analysis due to the heterogeneity of the duration of follow-up reported in the different trials.Our analysis is relevant for patients deemed suitable for intervention and did not address the efficacy of medical management alone in the prevention of stroke amongst this population.

Conclusions
Carotid artery disease is one of the major causes of stroke.CAS and CEA are the two revascularization modalities available for the prevention of stroke in this population.Our analysis demonstrated similar efficacy of the two modalities in terms of the composite end point of death/MI/stroke.CAS is a reasonable alternative to CEA with the additional benefit of decreased risk of MI and cranial nerve palsy.The outcomes of the two interventions are however greatly operator-dependent.

FIGURE 1 :
FIGURE 1: Search strategy and study selection per PRISMA flow diagram.

FIGURE 2 :
FIGURE 2: Revised Cochrane Collaboration's tool for quality assessment in trials comparing CAS to CEA.CAS: carotid artery stenting, CEA: carotid artery endarterectomy

FIGURE 4 :FIGURE 5 :
FIGURE 4: Forest plot of the secondary outcomes of all-cause mortality, MI, and cranial nerve palsy